The ongoing spread of industrialization has resulted in environmental pollution that is harmful to human health. Because of this trend the threat to human health from many environmental hazards has become common in the general population. Cadmium (Cd) is an environmental pollutant exposure to which in the general population has been increasing due to Cd contamination of air, soil, and water via mining, fossil fuel burning, smoking, incineration of municipal waste, and its use in plastics, pigments, and fertilizers. Although, even low doses of Cd increase cancer risk, Cd itself is a poor mutagen suggesting an indirect mechanism for Cd-associated increase in genomic instability in exposed individuals. While specific molecular mechanisms for this increased cancer risk have been proposed, they do not explain the existence of individual susceptibility to developing cancer upon exposure to Cd. We have discovered that Cd treatment of human cells in culture increases DNA damage associated with Long Interspersed Element-1 (L1) retrotransposon. However, whether Cd exposure increases L1-induced DNA damage in vivo is not known. If it does, this finding would provide a plausible mechanism explaining the observed variation in individual susceptibility to cancer upon Cd exposure, because genomic content of L1 elements (and therefore their resulting DNA damage) varies significantly among human genomes. This variation combined with the Cd-induced suppression of the nucleotide excision repair (NER) pathway, which restricts L1 mobilization, suggest that collectively L1 DNA damage and NER polymorphisms may dictate individual cancer susceptibility upon Cd exposure. Using tissue culture approaches and a custom transgenic mouse model we will test whether cancer-associated polymorphisms in the NER genes differentially affect stimulation of L1 retrotransposition by Cd and whether Cd exposure increases L1 mobilization in vivo. Our findings will establish whether individuals carrying specific NER gene polymorphisms may be more susceptible to L1-induced damage upon exposure to Cd and whether Cd increases L1 retrotransposition in a tissue-specific manner.